WO2021041970A1 - Composés d'imidazolopyrazine inhibiteurs de perk - Google Patents

Composés d'imidazolopyrazine inhibiteurs de perk Download PDF

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Publication number
WO2021041970A1
WO2021041970A1 PCT/US2020/048614 US2020048614W WO2021041970A1 WO 2021041970 A1 WO2021041970 A1 WO 2021041970A1 US 2020048614 W US2020048614 W US 2020048614W WO 2021041970 A1 WO2021041970 A1 WO 2021041970A1
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Prior art keywords
pyrazin
amino
phenyl
methyl
imidazo
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PCT/US2020/048614
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English (en)
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Mark J. Mulvihill
An-Hu Li
Matthew David Surman
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Hibercell, Inc.
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Priority to US17/639,183 priority Critical patent/US20220348583A1/en
Publication of WO2021041970A1 publication Critical patent/WO2021041970A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • Embodiments of the present invention relate to novel imidazolopyrazine compounds, to pharmaceutical compositions comprising the compounds, to methods of using the compounds to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compounds.
  • the present invention is in the field of treatment of cancer and, other diseases and disorders involving protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).
  • PPKR protein kinase R
  • PERK an eIF2 kinase involved in the unfolded protein response (UPR) regulates protein synthesis, aids cells to alleviate the impact of endoplasmic reticulum stress and has been implicated in tumor genesis and cancer cell survival.
  • UTR unfolded protein response
  • Tumor cells thrive in a hostile microenvironment caused mainly by nutrient and oxygen limitation, high metabolic demand, and oxidative stress.
  • UPR endoplasmic reticulum
  • the UPR serves as a mechanism for cellular survival whereby cells are able to adapt to cope with ER stress, but under extreme stress the UPR switches the cellular machinery toward apoptosis, contributing to greater tumorigenic potential of cancer cells, tumor metastasis, tumor drug resistance, and the ability of cancer cells to avoid effective immune responses. Tumors are believed to utilize the UPR for survival under stressed conditions such as nutrient deprivation or treatment with chemotherapy.
  • Other stress stimuli that activate UPR include hypoxia, disruption of protein glycosylation, depletion of luminal ER calcium, or changes in ER redox status.
  • ER transmembrane sensors of the UPR There are three major ER transmembrane sensors of the UPR: 1) inositol requiring enzyme (IREla/IREip, encoded by ERN1 and ERN2, respectively); 2) PKR-like ER kinase (PERK, also known as PEK, encoded by EIF2AK3); and 3) the activating transcription factor 6a (encoded by ATF6).
  • IREla/IREip encoded by ERN1 and ERN2, respectively
  • PKR-like ER kinase PKR-like ER kinase
  • PEK also known as PEK, encoded by EIF2AK3
  • 3) the activating transcription factor 6a encoded by ATF6
  • Each of these three sensors is regulated similarly through binding of the ER luminal chaperone protein GRP78 or BiP (encoded by HSPA5).
  • BiP encoded by HSPA5
  • PERK is a type I transmembrane serine/threonine kinase and a member of a family of kinases that phosphorylate the eukaryotic translation initiation factor 2a (eIF2-a) and regulate translation initiation.
  • Other family members include HRI (EIF2AK1), PKR (EIF2AK2), and GCN2 (EIF2AK4).
  • EIF2AK1 eukaryotic translation initiation factor 2a
  • GCN2 GCN2
  • PERK is an ER transmembrane protein with a stress-sensing domain inside the ER lumen and a cytosolic kinase domain. Upon sensing misfolded proteins, PERK is activated by autophosphorylation and oligomerization through release of BiP/Grp78 from the stress- sensing domain. Activated PERK phosphorylates and activates its downstream substrate, eukaryotic initiation factor 2a (eIF2a), which inhibits the ribosome translation initiation complex in order to attenuate protein synthesis. This serves to prevent exacerbation of ER stress by preventing the accumulation of additional misfolded proteins.
  • eIF2a eukaryotic initiation factor 2a
  • activated eIF2a causes the translation of specific mRNAs involved in restoring ER homeostasis including activating transcription factor 4 (ATF4).
  • ATF4 mediates the transcription of certain UPR target genes including those for the endoplasmic- reticulum-associated protein degradation (ERAD) pathway proteins which target misfolded proteins for ubiquitination and degradation by the proteasome.
  • ATF4 also causes the expression of the transcription factor C/EBP homologous protein (CHoP), which sensitizes cells to ER stress-mediated apoptosis, providing a pathway for regulated removal of severely stressed cells by the organism.
  • C/EBP homologous protein C/EBP homologous protein
  • Phosphorylation of eIF2 results in reduced initiation of general translation due to a reduction in eIF2B exchange factor activity decreasing the amount of protein entering the ER (and thus the protein folding burden) and translational demand for ATP.
  • Phosphorylation of eIF2 also increases translation of some mRNAs in a gene specific manner including the transcription factor ATF4.
  • ATF4 transcriptional targets include numerous genes involved in cell adaptation and survival including several involved in protein folding, nutrient uptake, amino acid metabolism, redox homeostasis, and autophagy.
  • Selective inhibition of the PERK arm of the UPR is expected to profoundly affect tumor cell growth and survival. As such, compounds which inhibit PERK are believed to be useful in treating cancer.
  • Embodiments of the present invention provide a compound having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF 2 , or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; R 1 is one or more independent H, deuterium, halo, CN, NO2, alkyl, cycloalkyl, C0- 6 alkyl-O-C 1-12 alkyl, C 0-6 alky
  • the compounds of the present invention are inhibitors of PERK, and are believed to be useful in treating cancer.
  • the present invention provides a compound having the structure (I): wherein: Ar 1 is aryl, heteroaryl, or cycloalkyl, optionally substituted by one or more independent R 1 substituents; Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; Y is CR 3a R 3b , C(O), CF 2 , or CNOR 3bb ; R 3a is H, alkyl, or cycloalkyl; R 3b is H, alkyl, OR 3c , or NR 3d R 3e ; R 3bb is H or alkyl; R 4 is H, alkyl, or OH; X is CR 7 or N; R 1 is one or more independent H, deuterium, halo, CN, NO 2 , alkyl, cycloalkyl, C 0- 6 alkyl-O-C 1-12 alkyl, C 0-6 alkyl-OH, C 0-6 alkyl
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising the compound of the present invention, an anti-cancer agent and a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting the growth of a tumor comprising contacting a tumor cell with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, so as to thereby inhibit the growth of the tumor.
  • the present invention further provides a method of inhibiting the growth of a tumor comprising contacting a tumor cell with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, in combination with an anti-cancer agent, so as to thereby inhibit the growth and/or metastasis of the tumor.
  • the present invention also provides a method of inhibiting PERK comprising contacting the tumor cell with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt.
  • the present invention yet further provides a compound having the following structure (Ia): wherein: Y is CR 3a R 3b ; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; R 1 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1- 12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 1 substituents; R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkylcycloalkyl, C 0- 6 alkyl-O-C 1-12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3c
  • the present invention yet further provides a compound having the following structure (Ib): wherein: X is CR 7 or N; R 1 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1- 12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 1 substituents; R 2 is one or more independent H, deuterium, halo, alkyl, cycloalkyl, C 0-6 alkyl-O-C 1- 12 alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl-O-C 3-12 cycloalkyl, optionally substituted by one or more independent G 2 substituents; R 3a is H or alkyl; R 3b is OR 3c or NR 3d R 3e ; R 3c , R 3d and R 3e
  • the present invention yet further provides a compound having the following structure (Ic): wherein: X is CR 7 ; R 1 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent G 1 substituents; R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent G 2 substituents; R 3b is OR 3c ; R 3c is H or alkyl, optionally substituted by one or more independent G 3 substituents; R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent G 4 substituents; R 6 is H, alkyl, CD 3 ,
  • the present invention yet further provides a compound having the following structure (Id): wherein: X is CR 7 ; R 1 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium, or halo; R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium or halo; R 5 is H, deuterium, halo, alkyl, cycloalkyl, or heterocycloalkyl, optionally substituted by one or more independent H, deuterium, halo, OH, or CN; R 6 is H, alkyl, CD 3 , or CF 3 ; R 7 is H, deuterium
  • the present invention yet further provides a compound having the following structure (Ie): wherein: X is CH; R 1 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium, or halo; R 2 is one or more independent H, deuterium, halo, alkyl, C 0-6 alkyl-OH, or C 0-6 alkyl- O-C 1-12 alkyl, optionally substituted by one or more independent H, deuterium or halo; R 5 is H, deuterium halo, methyl, ethyl, isopropyl, optionally substituted by one or more independent H, deuterium, C 1-6 alkyl, halo, OH, or CN; or a pharmaceutically acceptable salt thereof.
  • X is CH
  • R 1 is one or more independent H, deuterium,
  • R7 is H, chloro, methyl, ethyl, trifluoromethyl, heteroaryl, or CD3.
  • R1, for each occurrence is H, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, deuterium, fluoro, or chloro.
  • R2 is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, fluoro, chloro, CF3 or OCF3.
  • R5 is H, chloro, methyl, or CD3, ethyl, isopropyl, ,
  • R6 is H, methyl, ethyl, propyl, isopropyl, CD3, or CF3.
  • R6 is other than H.
  • G1, G2, G3, or G4 are each independently H, deuterium, halo, CN, NO2, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2.
  • G1, G2, G3, or G4 are each independently H, deuterium, halo, CN, NO2, C1-3alkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR8, NR8R9, C(O)R8, C(O)OR8, C(O)NR8R9, OC(O)R8, OC(O)OR8, OC(O)NR8R9, N(R10)C(O)R8, N(R10)C(O)OR8, N(R10)C(O)NR8R9, S(O)nR8, S(O)nOR8, S(O)nNR8R9, N(R10)S(O)nR8, N(R10)S(O)nOR8, or N(R10)S(O)nNR8R9, optionally substituted by one or more independent H, deuterium, halo, OH, CN, or NO2.
  • Ar1 is phenyl.
  • the present invention yet further provides a compound having the following structure (If): wherein: Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents; R 1 is each independently halo or alkyl, optionally substituted by one or more halogen substituents; R 2 is each independently halo, alkyl, or C 0-6 alkyl-O-C 1-12 alkyl, optionally substituted by one or more halogen substituents; R 5 is alkyl or cycloalkyl, optionally substituted by one or more deuterium, hydroxyl, or methyl substituents; R 6 is H or alkyl; R 7 is H, halo, or alkyl, optionally substituted by one or more halogen substituents; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • Ar 2 is aryl or heteroaryl, optionally substituted by one or more independent R 2 substituents
  • R 1 is each independently halo or alkyl,
  • R1 is chloro, fluoro, methyl, or trifluoromethyl.
  • p is 2.
  • R1, for each occurrence is fluoro, methyl, or trifluoromethyl.
  • Ar2 is phenyl.
  • Ar2 is phenyl, optionally substituted by one substituent selected from R2.
  • R2 is methyl, ethyl, fluoro, or trifluoromethoxy.
  • Ar2 is phenyl, optionally substituted by two substituents each independently selected from R2. [0045] In some embodiments, R2, for each occurrence, is fluoro or methyl. [0046] In some embodiments, Ar2 is pyridyl, optionally substituted by one substituent selected from R2. [0047] In some embodiments, R2 is methyl. [0048] In some embodiments, R5 is methyl, CD3, [0049] In some embodiments, R6 is H or methyl. [0050] In some embodiments, R7 is H, chloro, methyl, or trifluoromethyl.
  • the compound is selected from: N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (R)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; (S)-N-(4-(8-amino-3-methylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide; N-(4-(8-amino-3,6-dimethylimidazo[1,5-a]pyrazin-1-yl)-3-methylphenyl)-2-(3- fluorophenyl)-2-hydroxyacetamide;
  • Embodiments of the present invention futher provide a pharmaceutical composition, comprising a compound or a pharmaceutically acceptable salt thereof including one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Embodiments of the present invention futher provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds, or a pharmaceutically acceptable salt thereof.
  • Embodiments of the present invention futher provide a method of treating cancer in a patient comprising administering to a patient in need thereof an effective amount of any of the above compounds in combination with an anti-cancer agent, or pharmaceutically acceptable salts thereof.
  • Embodiments of the present invention futher provide a compound or pharmaceutically acceptable salt thereof for use in therapy.
  • Embodiments of the present invention futher provide a compound or pharmaceutically acceptable salt thereof according to any of the compounds for use in the treatment of cancer.
  • the cancer is particularly pancreatic cancer, melanoma, or breast cancer, including BrCa positive breast cancer.
  • Embodiments of the present invention futher provide a method of treating a disease in a patient in need of such treatment, said method comprising administering a PERK kinase modulating compound according to any of the above compounds, or a pharmaceutically acceptable salt thereof, wherein the disease is cancer.
  • the present invention provides a method of treating cancer in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of formula I, Ia, Ib, Ic Id, or Ie, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method of inhibiting PERK activity resulting in antitumor activity in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound of formula I, Ia, Ib, Ic, Id, or Ie, or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the compound and/or anti-cancer agent is orally administered to the subject. In some embodiments of any of the above methods or uses, the compound and/or anti-cancer agent is administered to the subject. [0061]
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemia, lymphoma, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include multiple myeloma, blood cancers, lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g. ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g.
  • non-small cell lung carcinoma squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma.
  • Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer
  • a “symptom” associated with cancer includes any clinical or laboratory manifestation associated with the cancer and is not limited to what the subject can feel or observe.
  • “treating”, e.g. of a cancer encompasses inducing prevention, inhibition, regression, or stasis of the disease or a symptom or condition associated with the cancer.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including racemates, enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • the enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • the compounds of the present invention may have spontaneous tautomeric forms. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • hydrogen atoms are not shown for carbon atoms having less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
  • This invention also provides isotopic variants of the compounds disclosed herein, including wherein the isotopic atom is 2H, 3H, 13C, 14C, 15N, and/or 18O. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms. [0069] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium); carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N, and the like.
  • a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.
  • the structures described in the embodiments of the methods hereinabove can be the same as the structures of the compounds described hereinabove.
  • Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
  • the subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C-13 and C- 14.
  • any notation of a carbon in structures throughout this application when used without further notation, are intended to represent all isotopes of carbon, such as 12C, 13C, or 14C. Furthermore, any compounds containing 13C or 14C may specifically have the structure of any of the compounds disclosed herein.
  • any notation of a hydrogen in structures throughout this application when used without further notation, are intended to represent all isotopes of hydrogen, such as 1H, 2H, or 3H. Furthermore, any compounds containing 2H or 3H may specifically have the structure of any of the compounds disclosed herein.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
  • the substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, heteroalkyl, monocycle, bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • substituents and substitution patterns on the compounds used in the method of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result.
  • C0-4alkyl for example is used to mean an alkyl having 0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration.
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-Cn as in “C1–Cn alkyl” is defined to include groups having 1, 2ising, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on.
  • An embodiment can be C1-C12 alkyl, C2-C12 alkyl, C3-C12 alkyl, C4-C12 alkyl and so on.
  • Alkoxy or “Alkoxyl” represents an alkyl group as described above attached through an oxygen bridge.
  • an alkoxy group is represented by C0-nalkyl-O-C0-malkyl in which oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • oxygen is a bridge between 0, 1, 2ising, n-1, m-1, n or m carbons in a linear or branched arrangement.
  • n zero
  • -O-C0-malkyl is attached directly to the preceding moiety.
  • m zero
  • alkoxy group is “C0-nalkyl-OH.” Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, tert-butoxy and so on.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present.
  • C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C6 alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on. [0085] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non- aromatic carbon-carbon triple bonds may be present.
  • C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C2-C6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C2-Cn alkynyl.
  • An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on [0086]
  • Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10-membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N- oxides thereof are also encompassed by this definition.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • monocycle includes any stable polyatomic carbon ring of up to 12 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aromatic monocycle elements examples include but are not limited to: phenyl.
  • “bicycle” includes any stable polyatomic carbon ring of up to 12 atoms that is fused to a polyatomic carbon ring of up to 12 atoms with each ring being independently unsubstituted or substituted.
  • non-aromatic bicycle elements examples include but are not limited to: decahydronaphthalene.
  • aromatic bicycle elements examples include but are not limited to: naphthalene.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p- toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non- aromatic, it is understood that attachment is via the aromatic ring.
  • polycyclic refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p- trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3- phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 12 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • alkylheteroaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above.
  • alkylheteroaryl is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group.
  • alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.
  • heterocycle or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4- dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.
  • the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • halogen or “halo” refers to F, Cl, Br, and I.
  • carbonyl refers to a carbon atom double bonded to oxygen.
  • a carbonyl group is denoted as RxC(O)Ry where Rx and Ry are bonded to the carbonyl carbon atom.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only methods by which to synthesize or obtain the desired compounds.
  • a pharmaceutical composition comprises the compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically active agent means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.
  • the compounds used in the method of the present invention may be in a salt form.
  • a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).
  • the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2- deoxyglucose, etc. and any other physiologically non-toxic basic substance.
  • “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers/diluents. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. [0123] For oral administration in liquid dosage form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • parenteral solutions can contain preservatives.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the compounds used in the method of the present invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
  • Parenteral and intravenous forms may also include minerals and other materials such as solutol and/or ethanol to make them compatible with the type of injection or delivery system chosen.
  • the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.
  • Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release of the active ingredient compounds before they reach the small intestine.
  • PERK In Vitro Activity Assay [0136] In vitro Inhibition of PERK Enzyme Activity (isolated) Recombinant human EIF2AK2 (PKR) catalytic domain (amino acids 252-551), EIF2AK3 (PERK) catalytic domain (amino acids 536 - 1116), GFP-eIF2a substrate, and Terbium-labelled phospho-eIF2a antibody is obtained (Invitrogen, Carlsbad, CA). [0137] Express and purify HIS-SUMO-GCN2 catalytic domain (amino acids 584 - 1019) from E. coli.
  • PKR assays contain 14 ng/mLenzyme and 2.5 mM ATP (Km, -2.5 mM), PERK assays contain 62.5 ng/mL enzyme and 1.5 mM ATP (Km. app -1.5 uM), and GCN2 assays contain 3 nM enzyme and 90 mM ATP (Km, -200 uM).
  • test compound initiates the reaction by addition of enzyme, and incubate at room temperature for 45 minutes. Stop the reaction by addition of EDTA to a final concentration of 10 mM, add Terbium-labelled phospho-eIF2a antibody at a final concentration of 2 nM, and incubate for 90 minutes. Monitor the resulting fluorescence in an EnVison® Multilabel reader (PerkinElmer, Waltham, MA).
  • PERK Cellular Assay Stable cell lines were created in HEK293 cells using lentiviral particles harboring an expression vector for GFP- eIF2a. Cells were selected using puromycin and enriched using fluorescence activated cell sorting against GFP. HEK293-EGFP-eIF2a cells were plated at 5000 cells/well in 384-well assay plates and incubated overnight at 37°C, 5% CO2. Inhibitor compounds were added to the wells by Echo acoustic dispensing and incubated for 30 minutes at 37°C, 5% CO2 prior to induction of ER stress by addition of tunicamycin to 1mM for 2 hours.
  • Table 1 Biochemical and cellular IC 50 data of Compounds of Formula I:
  • the reaction mixture was purged with argon for 10 min.
  • Palladium(II) acetate (5.77 g, 25.7 mmol) was added, and the mixture was purged with argon for 10 min.
  • the reaction mixture was heated at 95 °C with stirring for 16 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with methyl tert-butyl ether (4 ⁇ 250 mL). The filtrate was washed with water (2 ⁇ 500 mL) and brine (2 ⁇ 250 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 2 Synthesis of 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-1.3): To a stirred solution of methyl 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetate (B1- 2.1, 28 g, 119 mmol) in THF (70 mL), Water (20 mL), MeOH (50 mL), at room temperature LiOH (6.00 g, 143 mmol) was added and resulting reaction mixture was stirred for 12 h at same temperature. After this, the reaction mixture was concentrated under reduced pressure to get crude, which was quenched with water (100 mL).
  • Step- 3 Synthesis of 2-acetoxy-2-(3-(trifluoromethyl)phenyl)acetic acid (B-2.8): To a stirred solution of acetyl chloride (50 mL) at 0 °C was added 2-hydroxy-2-(3- trifluoro methyl)phenyl)acetic acid (B-1.3, 25.00 g, 113 mmol) portion wise over a period of 30 min. at same temperature. The reaction mixture was allowed to warm to room temperature and stirred for 1 h.
  • Step-2 Synthesis of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2- oxoethyl acetate (C-1.1): To a solution of 2-acetoxy-2-(3-fluorophenyl)acetic acid (B-2.3, 0.558 g, 2.63 mmol) and 4-bromo-3-fluoroaniline (A-1.3, 0.600 g, 3.16 mmol) in tetrahydrofuran (20 mL) were added N,N-diisopropylethylamine (0.90 mL, 5.3 mmol) followed by 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (1.50 g, 3.94 mmol) at room temperature and stirred for 16 h.
  • HATU 1- [bis(d
  • Step-3 Synthesis of 2-((3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)amino)-1-(3-fluorophenyl)-2-oxoethyl acetate (C-2.1): To a stirred solution of 2-((4-bromo-3-fluorophenyl)amino)-1-(3-fluorophenyl)-2- oxoethyl acetate (C-1.1, 0.10 g, 0.26 mmol) in 1,4-dioxane (3.0 mL) under argon atmosphere were added bis(pinacolato)diboron (0.13 g, 0.52 mmol) and potassium acetate (51 mg, 0.52 mmol.
  • reaction mixture was purged with argon for 10 min.
  • 1,1- Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.5 mg, 0.01 mmol) was added and the mixture was purged with argon for 10 min.
  • the reaction mixture was exposed to microwave irradiation (SEM Company) at 100 °C for 1 h. After this time, the reaction mixture was allowed to cool to room temperature, passed through a bed of diatomaceous earth, and washed with ethyl acetate (2 ⁇ 15 mL). The filtrate was washed with water (2 ⁇ 10 mL) and brine (2 ⁇ 10 mL).
  • reaction mixture was allowed to warm to room temperature and stirred for 12 h. After this time, the reaction mixture was diluted with methylene chloride (6.0 mL) and washed with water (4 ⁇ 4 mL) and brine (4 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step-1 Synthesis of (3-Chloro-5-methylpyrazin-2-yl)methanamine (E-2.1): To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (E-1.1, 1.00 g, 6.51 mmol) in acetic acid (20.0 mL) was added Raney Nickel (0.055 g, 0.65 mmol) under inert atmosphere. This reaction mixture was stirred for 20 h under hydrogen bladder pressure at room temperature.
  • Step-2 Synthesis of N-((3-Chloro-5-methylpyrazin-2-yl)methyl)acetamide (E- 4.1): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine (E-2.1, 0.652 g, 4.14 mmol) in methylene chloride (15.0 mL) were added N,N-diisopropylethylamine (362 mg, 2.80 mmol) followed by acetic anhydride (E-3.1, 320 mg, 0.84 mmol) at 0 o C and stirred for 14 h.
  • (3-chloro-5-methylpyrazin-2-yl)methanamine E-2.1, 0.652 g, 4.14 mmol
  • N,N-diisopropylethylamine 362 mg, 2.80 mmol
  • acetic anhydride E-3.1, 320 mg, 0.84 mmol
  • Step-3 Synthesis of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)acetamide (E-4.1, 0.65 g, 3.2 mmol) in acetonitrile (10.0 mL) were added N,N-dimethylformamide (0.3 mL) followed by phosphorous(V) oxychloride (1.5 g, 9.7 mmol) at 0 o C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • Step-4 Synthesis of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1): To a stirred solution of 8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-5.1, 0.561 g, 3.09 mmol) in N,N-dimethylformamide (8.0 mL) was added N-iodosuccinimide (0.835 g, 3.71 mmol) at room temperature. This reaction mixture was heated to 60 °C and stirred for 3 h.
  • Step-5 Synthesis of 1-iodo-3,6-dimethylimidazo[1,5-a]pyrazin-8-amine (E-7.1): A stirred solution of 1-iodo-8-chloro-3,6-dimethylimidazo[1,5-a]pyrazine (E-6.1, 0.701 g, 2.28 mmol) in 2.0 M ammonia in isopropanol (200.0 mL) was stirred in an autoclave for 48 h at 120 °C.
  • Step-2 Synthesis of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1): To a stirred solution of N-[(3-chloropyrazin-2-yl)methyl]-2,2,2-trideuterio-acetamide (F-3.1, 40.00 g, 212.7 mmol) in EtOAc (500 mL) were added dimethylformamide (20 mL) followed by phosphoryl chloride (81.3 g, 531.9 mmol) at 0 o C and the resulting reaction mixture was stirred for 16 h at room temperature. After this time, the reaction mixture was poured into mixture of sat.
  • F-4.1 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine
  • Step-3 Synthesis of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-5.1): To a stirred solution of 8-chloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F-4.1, 10.00 g, 58.8 mmol) in THF (350 mL) at -78 °C, n-butyllithium (2.5 M, 35.2 mL, 88.23 mmol) was added drop-wise and resulting reaction mixture was stirred for 10 min. at the same temperature.
  • methyl iodide (7.5 mL, 117.6 mmol) was added to it and stirred for 15 min. at -78 °C. After this time, the reaction mixture was quenched with sat. ammonium chloride solution (50 mL) at -78 °C. The reaction was warm to room temperature, stirred for 20 min. and extracted with EtOAc (2 x 200 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of 1-bromo-8-chloro-5-methyl-3- (trideuteriomethyl)imidazo[1,5-a]pyrazine (F-6.1): To a stirred solution of 8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 5.1, 25.00 g, 135 mmol) in dichloromethane (400 mL) was added N-bromosuccinimide (29.10 g, 163 mmol) portion-wise at room temperature and stirred for 1 h at same temperature.
  • Step-5 Synthesis of 1-bromo-5-methyl-3-(trideuteriomethyl)imidazo[1,5- a]pyrazin-8-amine (F-7.1): In a 5 L autoclave, 1-bromo-8-chloro-5-methyl-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-6.1, 30.00 g, 114 mmol) and ammonia (2 M in isopropanol) (2 L) was stirred for 40 h at 120 °C.
  • Step-2 Synthesis of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-6.2): To a stirred solution of 5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5-a]pyrazine (F- 5.2, 8.50 g, 41.4 mmol) in DMF (90 mL), N-bromosuccinimide (8.80 g, 49.7 mmol) was added portion-wise at room temperature and stirred for 4 h. After this time, the reaction mixture was quenched with ice cold water (200 mL).
  • Step-3 Synthesis of 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1): To a stirred solution of 1-bromo-5,8-dichloro-3-(trideuteriomethyl)imidazo[1,5- a]pyrazine (F-6.2, 11.20 g, 39.4 mmol) in 1,4-dioxane (150 mL) were added DIPEA (13.1 g, 78.9 mmol) followed by (2,4-dimethoxyphenyl)methanamine (13.90 g, 78.9 mmol) at room temperature.
  • Step-4 Synthesis of 1-bromo-5-chloro-3-(trideuteriomethyl)imidazo[1,5- a]pyrazin-8-amine (G-2.1): In a 1 L multi neck RBF, 1-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- (trideuteriomethyl)imidazo[1,5-a]pyrazin-8-amine (G-1.1, 15.00 g, 36.3 mmol.) and TFA (150 mL) was stirred for 3 h at 80 °C. After this time, the reaction mixture was cooled to room temperature and excess of TFA was distilled off to obtain crude viscous mass.
  • reaction mixture was cooled to room temperature and excess of solvent was distilled off under reduced pressure to obtain crude material.
  • the crude material was basified with aqueous ammonia solution, an aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-2 Synthesis of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3): To a stirred suspension of 2-aminomalonamide (I-2, 17.68 g, 151.16 mmol) and biacetyl (13 g, 151.16 mmol) in water (25 mL) was added aqueous NaOH (50% solution) (15 mL, 188.95 mmol) over a period of 20 min at 10 o C. After completion of addition, resulting reaction mixture was stirred for additional 2 h at the same temperature, pH of reaction mixture was adjusted to 6.0 (by acetic acid).
  • Step-3 Synthesis of 3-chloro-5,6-dimethylpyrazine-2-carbonitrile (I-4): To a stirred solution of 5,6-dimethyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (I-3, 12.00 g, 71.85 mmol) in chlorobenzene (60 mL) was added phosphoryl chloride (26.8 mL, 287.4 mmol) at room temperature. The resulting reaction mixture was heated to 60 o C and then added DIEA (37.57 mL, 215.55 mmol) dropwise over 30 min. Then the reaction mixture was stirred at 90 o C for another 3 h.
  • phosphoryl chloride 26.8 mL, 287.4 mmol
  • reaction mixture was cooled to room temperature, poured into mixture of sat. sodium bicarbonate solution (150 mL) and ethyl acetate (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-4 Synthesis of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5): In 450 mL autoclave, to a stirred solution of 3-chloro-5,6-dimethylpyrazine-2- carbonitrile (I-4, 8.00 g, 47.9 mmol) in acetic acid (150 mL) was added Raney Nickel (1.6 g) under inert atmosphere and resulting reaction mixture was stirred for 20 h under hydrogen atmosphere (100 psi) at room temperature. After this time, the reaction mixture was passed through the celite bed and washed with acetic acid (2 ⁇ 20 mL).
  • Step-5 Synthesis of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl)acetamide (I- 6): To a stirred solution of (3-chloro-5,6-dimethylpyrazin-2-yl)methanamine (I-5, 5.00 g, 29.13 mmol) in dichloromethane (50 mL) was added DIEA (10.15 mL, 58.27 mmol) followed by acetic anhydride (5.5 mL, 58.27 mmol) at 0 °C. After, that reaction mixture was stirred for 2 h.
  • Step-6 Synthesis of 8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-7): To a stirred solution of N-((3-chloro-5,6-dimethylpyrazin-2-yl)methyl) acetamide (I- 6, 5.00 g, 29.94 mmol.) in acetonitrile (100 mL) were added dimethylformamide (0.50 mL) followed by phosphoryl chloride (8.3 mL, 153.3 mmol) at 0 o C. This reaction mixture was heated to 80 °C and stirred for 2 h.
  • reaction mixture was cooled to room temperature and poured into mixture of saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-7 Synthesis of 1-bromo-8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I- 8): To a stirred solution of 8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I-7, 5.00 g, 25.64 mmol) in dimethylformamide (50 mL) was added N-bromosuccinimide (4.56 g, 25.64 mmol) at 0 °C and stirred for 1 h. After this time, the reaction mixture was diluted with water (150 mL) and EtOAc (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step-8 Synthesis of 1-bromo-8-chloro-3,5,6-trimethylimidazo[1,5-a]pyrazine (I- 9): In a 1 L autoclave, a mixture of 1-bromo-8-chloro-3,5,6-trimethylimidazo[1,5- a]pyrazine (I-8, 6.00 g, 21.81 mmol) and ammonia (2M in isopropanol) (500 mL) was stirred for 12 h at 120 °C.
  • Step-1 Synthesis of (3-chloro-5-methylpyrazin-2-yl)methanamine (J-2): To a stirred solution of 3-chloro-5-methylpyrazine-2-carbonitrile (J-1, 5.00 g, 3.26 mmol) in acetic acid (80.0 mL) was added Raney Nickel (1.55 g, 6.65 mmol.) under inert atmosphere.
  • reaction mixture was stirred for 20 h under hydrogen atmosphere ( ⁇ 30 psi) at room temperature. After this time, the reaction mixture was passed through a bed of diatomaceous earth, washed with EtOAc (2 ⁇ 100 mL). The organic layer was concentrated to obtain crude material, which was diluted with 2N hydrochloric acid (15 mL) and extracted with ethyl acetate (2 x 100 mL).
  • Step-2 Synthesis of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3- oxocyclobutanecarboxamide (J-4): To a stirred solution of (3-chloro-5-methylpyrazin-2-yl)methanamine hydrochloride (J-2, 3.00 g, 26.3 mmol) in dichloromethane (80 mL) were added N,N-diisopropylethylamine (22.9 mL, 131.5 mmol), T 3 P (50% in EtOAc) (12 mL, 39.47 mmol) followed by 3- oxocyclobutanecarboxylic acid (J-3, 5.10 g, 26.31 mmol) at 0 o C and stirred for 1 h.
  • 3- oxocyclobutanecarboxylic acid J-3, 5.10 g, 26.31 mmol
  • Step-3 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-5): To a stirred solution of N-((3-chloro-5-methylpyrazin-2-yl)methyl)-3- oxocyclobutanecarboxamide (J-4, 4.70 g, 18.5 mmol) in EtOAc (80 mL) were added dimethylformamide (3 mL) followed by phosphoryl chloride (5.3 mL, 55.7 mmol) at 0 o C. This reaction mixture was stirred at room temperature for 1 h.
  • Step-4 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-6): To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a] pyrazin-3- yl)cyclobutanone (J-5, 3.00 g, 12.7 mmol) in dimethylformamide (15 mL) was added N- Bromosuccinimide (2.21 g, 12.7 mmol.) at room temperature. This reaction mixture was stirred at room temperature for 40 min.
  • Step-5 Synthesis of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3-yl)-1- methylcyclobutanol (J-7): To a stirred solution of 3-(1-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazin-3- yl)cyclobutanone (J-6, 3.30 g, 10.57 mmol) in anhydrous THF (35 mL) was charged methylmagnesium chloride (3M in THF) (7.1 mL, 21.15 mmol) dropwise at -78 °C over a period of 15 min under N2 and resulting mixture was stirred at -78 °C for an additional 2 h.
  • methylmagnesium chloride (3M in THF)
  • reaction mixture was warmed to –20 °C for 30 min.
  • the mixture was cooled back to –78 °C, quenched with sat. NH 4 Cl (60 mL) at same temperature and then warmed to room temperature.
  • Step-6 Synthesis of 3-(8-amino-1-bromo-6-methylimidazo[1,5-a] pyrazin-3-yl)-1- methylcyclobutanol (J-8): In a 450 mL autoclave, a mixture of 3-(1-bromo-8-chloro-6-methylimidazo[1,5- a]pyrazin-3-yl)-1-methylcyclobutanol (J-7, 1.50 g, 4.54 mmol) and ammonia (2M in isopropanol) (150 mL) was stirred for 18 h at 120 °C.
  • Table 1 The compounds of formula I (Table 1) can be synthesized according to the procedures described in Scheme K: Table 1: Compounds of Formula I: References Adrian L. Smith et al., Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), J. Med. Chem., 2015, 58 (3), pp 1426–1441 Ron, D.; Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response Nat. Rev. Mol. Cell Biol.2007, 8, 519– 529 Shore, G. C.; Papa, F. R.; Oakes, S. A.
  • Table 1 Compounds of Formula I: References Adrian L. Smith et al., Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kina
  • the unfolded protein response from stress pathway to homeostatic regulation Science2011, 334, 1081– 1086 Vandewynckel, Y.P.; Laukens, D.; Geerts, A.; Bogaerts, E.; Paridaens, A.; Verhelst, X.; Jans sens, S.; Heindryckx, F.; van Vlierberghe, H.
  • PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis Mol. Cell. Biol. 2012, 32, 5129–5139 Bi, M.; Naczki, C.; Koritzinsky, M.; Fels, D.; Blais, J.; Hu, N.; Harding, H.; Novoa, I.; Varia, M.; Raleigh, J.;Scheuner, D.; Kaufman, R. J.; Bell, J.; Ron, D.; Wouters, B. G.; Koumenis, C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth EMBO J. 2005, 24, 3470–3481 Kim, I.; Xu, W.; Reed, J.

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Abstract

L'invention concerne des composés de formule (I) tels que présentés ci-dessous, des compositions et des procédés utiles pour inhiber PERK et pour traiter des états, des maladies et des troubles apparentés.
PCT/US2020/048614 2019-08-29 2020-08-28 Composés d'imidazolopyrazine inhibiteurs de perk WO2021041970A1 (fr)

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CN113929633A (zh) * 2021-10-27 2022-01-14 山东大学 一种法匹拉韦的合成方法及其应用
WO2023025912A1 (fr) 2021-08-25 2023-03-02 Alesta Therapeutics BV Utilisation d'inhibiteurs de gcn2 dans le traitement du cancer

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023025912A1 (fr) 2021-08-25 2023-03-02 Alesta Therapeutics BV Utilisation d'inhibiteurs de gcn2 dans le traitement du cancer
CN113929633A (zh) * 2021-10-27 2022-01-14 山东大学 一种法匹拉韦的合成方法及其应用
CN113831255A (zh) * 2021-11-25 2021-12-24 山东诚创蓝海医药科技有限公司 一种2-氨基丙二酰胺的制备方法
CN113831255B (zh) * 2021-11-25 2022-03-11 山东诚创蓝海医药科技有限公司 一种2-氨基丙二酰胺的制备方法

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